Project Summary Transcriptional control, targeted modification, and excision of HIV-1 in the brain Human Immunodeficiency Virus type 1 (HIV) is a lentivirus that causes a persistent infection, which ultimately results in the demise of immune regulatory cells. HIV infection is inexorably followed by diseases attributable to acquired immunodeficiency syndrome (AIDS) (1, 2). Clearance of HIV infection by the immune system is inefficient and thus allows for integration of proviral DNA into the genome of host cells, which ultimately results in viral latency (3). Latency in HIV infection has immense importance because infectious virus can remain protected from immune mediated clearance and re-emerge after a long absence, often years following initial infection, regardless of current therapeutic strategies. One location of latent virus is in the brain, an area that is relatively compartmentalized from the body via the blood brain barrier. HIV infection in the brain results in NeuroAIDS, a pathological condition that is marked by HIV associated dementia (HAD) (4). Indubitably, devising a method that would abrogate the viruses' ability to remain in the brain of infected individuals could prove therapeutically significant and impacting. We propose here to contrast three distinct, yet complimentary, approaches capable of specifically targeting HIV in the brain and either epigenetically silencing, directing Cytosine to Thymine (C->T) mutations, or excising the virus from integrated sites. The three distinct approaches which we will develop here are; (1) small non-coding RNA directed epigenetic silencing of HIV-1 (5), (2) BREC1 enzymatic cutting of HIV (6), and (3) a newly developed Zinc Finger targeted silencing and APOBEC1 mediated cytosine to thymine mutation approach.